Efficacy of a New Low-Dose Oral

Contraceptive With Drospirenone in

Premenstrual Dysphoric Disorder
Kimberly A. Yonkers, MD, Candace Brown, RN, PharmD, Teri B. Pearlstein,
Marie Foegh, MD, DSc, Carole Sampson-Landers, MD, and Andrea Rapkin,
Objective: To compare the efficacy of a new low-dose oral
contraceptive pill (OCP) formulation with placebo in reducing symptoms of premenstrual dysphoric disorder.
Methods: This multicenter, double-blind, randomized
clinical trial consisted of 2 run-in and 3 treatment cycles
with daily symptom charting; 450 women with symptoms
of premenstrual dysphoric disorder were randomized to
either placebo or an OCP formulation containing drospirenone 3 mg and ethinyl estradiol 20 g. Hormones
were administered for 24 days, followed by 4 days of
inactive pills (24/4).
Results: Scores on the total Daily Record of Severity of
Problems decreased by 37.49 in the drospirenone/ethinyl
estradiol group and by 29.99 in the placebo group (adjusted mean difference 7.5, 95% confidence interval [CI]
11.2 to 3.8; P .001 by rank analysis of covariance).
Mood symptom scores were reduced by 19.2 and 15.3 in
active-treatment and placebo groups, respectively (adjusted
mean difference 3.9, 95% CI 5.84 to 2.01; P .003);
physical symptom scores were reduced by 10.7 and 8.6
in active-treatment and placebo groups, respectively (adFrom the Departments of Psychiatry and Epidemiology and Public Health, Yale
University, New Haven, Connecticut; Departments of Pharmacy, Obstetrics and
Gynecology, and Psychiatry, University of Tennessee Health Science Center,
Memphis, Tennessee; Department of Psychiatry and Human Behavior, Brown
Medical School, Providence, Rhode Island; Berlex Incorporated, Montville, New
Jersey; and Department of Obstetrics and Gynecology, University of California
Los Angeles, Los Angeles, California.
Corresponding author: Kimberly A. Yonkers, MD, Departments of Psychiatry and
Epidemiology and Public Health, Yale University School of Medicine, 142 Temple
Street, Suite 301, New Haven, CT 06510; e-mail: kimberly.yonkers@yale.edu.
Financial Disclosure
Schering AG (Berlin, Germany) provided the financial support for this study,
which was conducted by Berlex Incorporated (U.S. affiliate). Drs. Foegh and
Sampson-Landers are employees of Berlex Incorporated and own stock and hold
stock options in Schering AG.
2005 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/05

492

VOL. 106, NO. 3, SEPTEMBER 2005

MD,
MD

justed mean difference 2.1, 95% CI 3.3 to 0.95; P

.001); and behavioral symptom scores were reduced by
7.7 and 6.2 in active-treatment and placebo groups,
respectively (adjusted mean difference 1.5, 95% CI 2.251
to 0.727; P .001). Response, defined as a 50% decrease
in daily symptom scores, occurred in 48% of the activetreatment group and 36% of the placebo group (relative risk
1.7, 95% CI 1.1 to 2.6; P .015) and corresponds to a
number-needed-to-treat of 8 patients.
Conclusion: A 24/4 regimen of drospirenone 3 mg and
ethinyl estradiol 20 g improves symptoms associated with
premenstrual dysphoric disorder.
(Obstet Gynecol 2005;106:492501)

Level of Evidence: I

lthough many women encounter mildly troublesome premenstrual symptoms during their reproductive years, approximately 35% of women suffer
from the more debilitating condition, premenstrual dysphoric disorder. Women with premenstrual dysphoric
disorder experience moderate-to-severe mood, behavioral, and physical symptoms that disrupt their lives at
home or work.1,2 Given that women with premenstrual
dysphoric disorder face symptoms on a monthly basis
from their early 20s until menopause (age 51), they
may be symptomatic for about 2,800 days, or 7 8 years,
over their lifetime. This extended symptomatic period,
in addition to the prevalence of the illness, places
premenstrual dysphoric disorder in a similar burden-ofillness category as dysthymic disorder, major depression, and other common medical disorders.3
The biological processes underlying premenstrual dysphoric disorder are not known. However,
symptoms are diminished by suppressing ovarian
activity4,5 and can be provoked in medically ovariectomized women by exposing them to exogenous
OBSTETRICS & GYNECOLOGY

gonadal steroids.6 Combined oral contraceptive pills

(OCPs) can prevent ovulation and replace endogenous fluctuations of ovarian steroids with stable hormone levels. For this reason combined OCPs are used
to treat premenstrual symptoms.7 However, significant differences between active medication and placebo were not found in the only 2 published randomized, placebo-controlled trials.8,9
The purpose of this study was to compare posttreatment symptom scores among women suffering
from premenstrual dysphoric disorder who were randomized to either a new OCP formulation containing
drospirenone 3 mg and ethinyl estradiol 20 g or
placebo. Drospirenone, a novel progestin with antimineralocorticoid and antiandrogenic activity, is an
analogue of spironolactone, which has been shown to
ameliorate symptoms of premenstrual syndrome.10
The active hormones were administered for 24 consecutive days rather than the conventional 21 days in
a 28-day cycle (21/7). This new treatment platform is
associated with greater suppression of follicle development and a more stable hormonal milieu than is
found with the standard 21/7 regimen.11,12 Given the
prior efficacy of spironolactone for premenstrual
symptoms, the follicular suppression found with a
24/4 regimen as well as the lower estrogen dose, we
hypothesized that women randomized to active treatment would experience fewer premenstrual symptoms than women randomized to placebo.

MATERIALS AND METHODS

This double-blind, randomized, placebo-controlled,
parallel-design study consisted of 7 visits: a screening
visit, 2 single-menstrual-cycle qualification visits, 3
single-menstrual-cycle treatment visits in which subjects took either drospirenone 3 mg/ethinyl estradiol
20 g or placebo, and an end-of-treatment visit.
(Participant flow is shown in Fig. 1.) Subjects used
barrier contraception throughout the study. All protocols were approved by a site or central institutional
review board, and all subjects provided verbal and
written informed consent.
Subjects were recruited from 64 centers in the
United States; recruitment and follow-up occurred
from January 2001 through September 2003. Eligibility criteria included 1) aged 18 to 40 years; 2) a
diagnosis of premenstrual dysphoric disorder according to the Diagnostic and Statistical Manual of Mental
Disorders, 4th edition2; 3) no depressive, anxiety,
eating, bipolar, psychotic, somatoform, dysthymic, or
drug/alcohol use disorders during the last 2 years; 4)
no OCP use for the 3 months before study entry; 5)
no concurrent therapy for premenstrual dysphoric
disorder; 6) regular menstrual cycles (2534 days); 7)
no contraindication to OCP treatment; 8) a nonsuspiVOL. 106, NO. 3, SEPTEMBER 2005

cious Pap test within the prior 6 months; and 9) no

current pregnancy.
To meet criteria for randomization, subjects were
required to have 2 consecutive menstrual cycles of
moderate-to-severe premenstrual symptoms and minimal-to-no follicular-phase symptoms immediately
before beginning the 3 double-blind placebo or active
treatment cycles. Premenstrual dysphoric disorder
severity criteria included 1) a premenstrual-phase
(days 5 to 1 before bleeding) daily average of 3.0 or
greater for 5 distinct items in the Daily Record of
Severity of Problems13; 2) a premenstrual-phase daily
average that was twice as high as the corresponding
postmenstrual-phase average for the 5 distinct items;
3) a postmenstrual phase (days 6 10) daily average of
2.5 or less for each of the 11 distinct items in the Daily
Record of Severity of Problems; and 4) a score of 3 or
greater on one Daily Record of Severity of Problems
functional impairment item for at least 2 premenstrual
days.
Randomization numbers were generated in fixed
blocks of 4 and were allocated in a 1:1 ratio. The
sponsors central coordinating group assigned and
sent out the blocks in advance of enrollment. Because
we anticipated that relatively few patients would be
enrolled per site, patients were not stratified by site.
The Daily Record of Severity of Problems scale
has 24 questions that are grouped into 11 distinct
symptom items and 3 functional impairment items,
which are self-rated on a 6-point scale from 1 (not at
all) to 6 (extreme). The averages of the last 5 days
before menses for the 11 distinct symptom items were
summed and constitute the total Daily Record of
Severity of Problems symptom score. The a priori
primary efficacy variable was the difference between
the average luteal phase Daily Record of Severity of
Problems total scores from the 2 qualification cycles
and the average luteal phase Daily Record of Severity
of Problems total scores from the 3 treatment cycles.
Responders were defined as subjects who had a reduction from baseline of 50% or greater in their total
Daily Record of Severity of Problems symptom score.
Secondary outcome measures included each of
the 11 individual items from the Daily Record of
Severity of Problems, the 3 functional impairment
items from this scale, the Premenstrual Tension Scales
observer-rated and self-rated questionnaires,14 the Endicott Quality of Life Enjoyment and Satisfaction
Questionnaire,15 and the Clinical Global ImpressionImprovement scale.16 Scores for both Premenstrual
Tension Scales range between 0 and 36; a premenstrual score of 18 21 is typically found in patients
with premenstrual dysphoric disorder.17 Baseline and
treatment-related quality of life were assessed with the
general activities subscale of the Endicott Quality of

Yonkers et al

Drospirenone OCP and Premenstrual Symptoms

493

Fig. 1. Participant flow. Drospirenone/EE drospirenone 3 mg ethinyl estradiol 20 g. * Other included 3 subjects
moving away, 1 sponsoring company employee, 1 suspected pregnancy, and 2 subject screens that failed in error. One
woman discontinued the study before taking any medication; therefore, 449 women were included in the full analysis set,
and 231 women started the active drug. Other included 1 patient out of her study visit window for a study visit, 1 with
noncompliance, 1 with loss of the diary and month 3 of medication, and 1 moving out of state.
Yonkers. Drospirenone OCP and Premenstrual Symptoms. Obstet Gynecol 2005.

Life Enjoyment and Satisfaction Questionnaire.15 This

self-report measure includes 14 items rated on a scale
of 15 (range 14 70), with higher scores indicating a
better quality of life. The Clinical Global ImpressionImprovement scale is a single-item measure that
observers and subjects used to rate global improvement from baseline on a scale of 1 (very much
improved) to 7 (very much worse).16
After screening, subjects were administered the
Structured Clinical Interview for the Diagnostic and
Statistical Manual of Mental Disorders, 4th edition,18 to
determine the presence of exclusionary psychiatric
494

Yonkers et al

diagnoses. Daily ratings were kept throughout the study.

Clinical Global Impression-Improvement scales were
completed during each treatment visit in each cycle.
The other scales were completed once before randomization and after the first and third treatment cycles.
Women underwent general physical and pelvic
examinations and had routine blood, urine, and pregnancy tests performed during the diagnostic period and
after the 3 treatment cycles. Vital signs, weight, and
adverse event information were collected at all visits.
Randomized subjects started drospirenone/ethinyl estradiol or matching placebo on day 1 or 2 of the

Drospirenone OCP and Premenstrual Symptoms

OBSTETRICS & GYNECOLOGY

menstrual cycle and continued until day 24. The last 4

days of the pill pack consisted of inert placebo pills for
both groups. Subjects took pills for 3 menstrual cycles.
Data were analyzed from the intent-to-treat cohort that included all randomized subjects who took
at least 1 dose of study pills. Study centers were
pooled from largest to smallest until the pooled center
had more than 5 subjects with postbaseline data in
each treatment group. No pooled center had more
than 15% of the total number of subjects. Analysis of
variance (ANOVA) was used to compare differences
in baseline scores between the active-treatment and
placebo groups. The ANOVA model included terms
for treatment assignment and pooled center. Comparisons of categorical measures were made using a
generalized Cochran Mantel Haenszel test stratified
by pooled center.
Daily Record of Severity of Problems scores from
the final 5 days of the menstrual cycle were averaged
to obtain mean pretreatment (qualifying cycles 1 and
2) or posttreatment (treatment cycles 13) individualitem and total values. Missing data points were imputed by averaging days bordering the missing value.
There were fewer than 0.25% missing data points,
which were distributed equally in both groups. The
individual-item and summary scores were carried
forward for noncompleters. Differences between daily
ratings for the 2 treatment groups were estimated
initially using an analysis of covariance (ANCOVA)
model containing terms for treatment and pooled
center, with the baseline value as a covariate. Normality of the residuals was assessed with the Shapiro-Wilk
statistic. Because the data violated the normality
assumption in many instances, analyses were repeated using a rank ANCOVA with the same terms.
In these instances, the rank ANCOVA was reported.
The Fisher exact test was used for analyses where cells
included fewer than 10 observations.
Rates of response ( 50% decrease in daily
ratings after treatment) in both groups were compared
using logistic regression, with additional terms for
treatment and pooled center. The addition of body
mass index and age to the logistic model did not add
explanatory power (P value for regression coefficients
0.5) and therefore were not included in the final
model.
A similar statistical approach was used for additional secondary measures. For subjects who dropped
out of the trial, scores were carried forward to the end
of the double-blind treatment phase. Differences
among continuous measures were estimated using
ANCOVA models that included terms for treatment
assignment, pooled center, and baseline score as a
covariate. If the assumption of homogeneity of slopes
was violated at the 0.05 level, a supportive rank
VOL. 106, NO. 3, SEPTEMBER 2005

ANCOVA was performed and was reported. We

estimated that by recruiting 408 subjects, we would
have 90% power to show a significant (P .05)
difference between groups of at least 6.5 (standard
deviation 18) points on the total Daily Record of
Severity of Problems, if a difference truly exists. For a
repeated measures design, we assumed that 80% of
the randomized subjects would have at least one
response during the treatment period. Data were
analyzed with SAS 8.12 (SAS Institute, Cary, NC).

RESULTS
Women were recruited by advertisement and referral.
Of the 3,496 women who requested participation, 449
subjects were included in the intent-to-treat analysis.
Screening flow is shown in Figure 1. Eligibility among
women interested in participation was similar to that
found in other clinical trials of premenstrual dysphoric disorder.13,17,19,20 The only statistically significant
differences in baseline characteristics between the
drospirenone/ethinyl estradiol and placebo groups
were in mean age (31.0 versus 32.0 years, respectively, P
.048) and body mass index (26.1 versus 25.1 kg/m2,
respectively, P .015) (Table 1). Of the subjects randomized, 161 (69.4%) in the drospirenone/ethinyl estradiol group and 167 (76.6%) in the placebo group completed the study. There were no statistically significant
differences (P .473 by ANOVA) in the main outcome
measure between treatment and placebo groups for
those women who failed to complete the study. There
was no significant difference in the number of women
who completed active treatment and those who received placebo (P .09 by Fisher exact test).
The on-treatment differences in cycle lengths for
patients receiving active treatment and placebo were
small and nonsignificant (27.3 days for drospirenone/
Table 1. Demographic and Baseline Characteristics
Treatment Group
Characteristics
Age (y)
Race/ethnicity
White
Black
Hispanic
Asian
Other
Weight (kg)
Height (cm)
Body mass index
Cycle length (d)

Drospirenone/Ethinyl
Estradiol (n 231*)

Placebo
(n 218)

31.0 5.6

32.0 5.5

176 (76.2)
25 (10.8)
22 (9.5)
2 (0.9)
6 (2.6)
70.6 13.2
166.0 6.2
26.1 4.6
28.7 2.0

170 (78.0)
20 (9.2)
21 (9.6)
3 (1.4)
4 (1.8)
68.4 12.9
166.4 7.0
25.1 4.3
28.8 1.7

Data are expressed as mean standard deviation or n (%).

* One subject randomized to active treatment who discontinued
before taking any medication is not included in the full analysis set.

P .05.

Yonkers et al

Drospirenone OCP and Premenstrual Symptoms

495

ethinyl estradiol and 27.6 days for placebo; P .23).

Bleeding began an average of 3 days after cessation of
active pills when subjects took drospirenone/ethinyl
estradiol; therefore, approximately 3 days of the
hormone-free interval were included in the premenstrual phase.
The total Daily Record of Severity of Problems
symptom score in subjects receiving drospirenone/
ethinyl estradiol decreased by 47%, from a mean (
standard deviation [SD]) of 77.40 ( 16.7) during the
qualification cycles to an average of 41.2 ( 17.3) for
the 3 treatment cycles; the corresponding reduction in
the placebo group was 38%, from 78.1 ( 17.8) to
48.1 ( 21.1). The estimated adjusted mean change
from baseline over 3 cycles in the total Daily Record
of Severity of Problems symptom score was 37.49
for the drospirenone/ethinyl group and 29.99 for
the placebo group, for an adjusted mean difference of
7.50 (95% confidence interval [CI] 11.2 to 3.8; P
.001 by rank ANCOVA). The estimated improvement was significantly greater for subjects assigned to
drospirenone/ethinyl estradiol than for those receiving placebo for all 11 distinct items in the Daily
Record of Severity of Problems (Table 2). When the
estimated difference was corrected for multiple testing
(n 11, P .005), differences between groups for
items tired/fatigued and slept more were no
longer statistically significant.
Symptoms from the Daily Record of Severity
were summed into clinically derived subscales reported by others.13,17,20 Active treatment reduced
physical symptoms by 10.7 points, compared with
8.6 points in the placebo group (adjusted mean
difference 2.1, 95% CI 3.3 to 0.95; P .001 by
rank ANCOVA). Similarly, mood symptoms were
decreased by 19.2 and 15.3 points in active-treatment and placebo groups, respectively (adjusted
mean difference 3.9, 95% CI 5.84 to 2.010; P
.003 by rank ANCOVA), and behavioral symptoms
improved by 7.7 and 6.2, in active-treatment and
placebo groups, respectively (adjusted mean difference 1.5, 95% CI 2.25 to 0.73; P .001).
To determine whether subjects experienced hormone withdrawal symptoms or a shift in their symptomatic period, we compared the total Daily Record
of Severity of Problems score from days 2124 (active
hormone administration) with that from days 2528
(placebo administration) for women assigned to drospirenone/ethinyl estradiol. Terms in the ANOVA
model included subject, pill pack, pill-pack
days, and the interaction of pill-pack days with pill
pack. There was no significant difference in modelestimated mean total Daily Record of Severity of
Problems scores between these 2 intervals (38.4
17.6 for days 2124 versus 39.6 18.8 for days
496

Yonkers et al

2528, 95% CI 3.19 to 0.12, P .069). This lack of

difference is particularly notable because, aside from
withdrawal, there is a tendency for women to experience more symptoms as menses approach.
Overall improvement according to the Clinical
Global Impression-Improvement observer-rated scale
was greater for subjects receiving active treatment
than for those in the placebo group (2.2 versus 2.5,
adjusted mean difference 0.30, 95% CI 0.55 to
0.05; P .004 by rank ANCOVA). Similarly,
self-rated improvement was greater in the activetreatment than in the placebo group (2.3 versus 2.5,
adjusted mean difference 0.26, 95% CI 0.53 to
0.008; P .014 by rank ANCOVA). Active treatment
was significantly more effective than placebo in observer-rated (adjusted mean difference 1.9, 95% CI
3.8 to .05; P .023 by rank ANCOVA) and
self-rated (3.5, 95% CI 5.7 to 1.3, P .004 by rank
ANCOVA) Premenstrual Tension Scales scores. The
median pretreatment and on-treatment values and the
adjusted mean differences between groups for the
Premenstrual Tension Scales are shown in Table 3.
Functional-impairment and quality-of-life domains were included as secondary outcome measures
(Table 3). Compared with the placebo group, the
subjects randomized to drospirenone/ethinyl estradiol experienced significant improvement in the functional items from the Daily Record of Severity of
Problems: productivity (adjusted mean difference
0.33, 95% CI 0.55 to 0.12; P .003 by rank
ANCOVA); enhanced enjoyment in social activities
(adjusted mean difference 0.34, 95% CI 0.55 to
0.12; P .003 by rank ANCOVA); and better
quality of relationships (adjusted mean difference
0.42, 95% CI 0.64 to 0.20; P .001 by rank
ANCOVA). Subjects using drospirenone/ethinyl estradiol reported statistically greater improvement in
items 114 of the Endicott Quality of Life Enjoyment
and Satisfaction Questionnaire (P .047 by rank
ANCOVA) compared with those subjects randomized to placebo, although statistical significance was
not achieved for medication satisfaction (item 15) and
overall life satisfaction (item 16). By cycle 3, 48.4%
(95% CI 41.1% to 55.8%) of actively treated and
36.1% (95% CI 29.3% to 43.3%) of placebo-treated
subjects met the criteria for response (odds ratio 1.7,
95% CI 1.1 to 2.6; P .015). The number-needed-totreat was 8 patients.
Adverse events considered by investigators to be
possibly related to the study drug occurred in 118
(51.1%) subjects in the drospirenone/ethinyl estradiol
group and 66 (30.3%) subjects in the placebo group.
Adverse events that occurred in 5% or more of either
treatment assignment are shown in Table 4. There

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Yonkers et al

Drospirenone OCP and Premenstrual Symptoms

497

9.7
4.2
8.5
8.4
3.9
3.8
4.2
7.6
6.8
7.3
13.3

13.4

Placebo

9.7
4.2
8.3
8.2
4.0
3.9
4.4
7.7
6.9
6.8

Drospirenone/Ethinyl
Estradiol

7.4

4.0
1.9
3.3
3.7
1.7
1.5
2.1
3.3
3.5
2.8

Drospirenone/Ethinyl
Estradiol

8.6

4.6
2.4
4.5
4.7
1.8
1.9
2.5
3.8
3.9
3.3

Placebo

Median Treatment Score

1.4

0.8
0.4
1.0
0.9
0.3
0.4
0.3
0.8
0.4
0.7

Adjusted Mean
Difference

to
to
to
to
to
to
to
to
to
to

0.30
0.23
0.57
0.49
0.10
0.15
0.07
0.35
0.12
0.35
2.11 to 0.77

1.38
0.66
1.43
1.36
0.52
0.58
0.51
1.32
0.79
1.15

95% CI

CI, confidence interval.

* Lower score indicates improvement.

Number 231; one subject randomized to active treatment who discontinued before taking any medication is not included in the full analysis set.

Number 218.

Unless otherwise noted, all P values are from rank analysis of covariance with terms for treatment, pooled center, and baseline score for the on-treatment comparisons.

Analysis of variance with terms for treatment and center; no violation of normality.

1a. Depressed, b. hopeless, c. worthless/guilty

2. Anxious/tense
3a. Mood swings, b. feel sensitive
4a. Angry/irritable, b. conflicts
5. Diminished interest
6. Difficulty concentrating
7. Tired/fatigued
8a. Increased appetite, b. food cravings
9a. Slept more, b. trouble sleeping
10. Overwhelmed/lack of control
11a. Breast tenderness, b. breast swelling, c. bloated
sensation, d. headache, e. muscle pain

Individual Symptom Items

Median Baseline Score

.001

.005
.001
.001
.001
.003
.001
.010
.010
.033
.001

Table 2. Changes in Individual Daily Rating Items* in the Daily Record of Severity of Problems With Drospirenone/Ethinyl Estradiol Versus Placebo

Yonkers et al

CI, confidence interval; DRSP, Daily Record of Severity of Problems; Q-LES-Q, Endicott Quality of Life Enjoyment and Satisfaction Questionnaire; PMTS, Premenstrual Tension Scales.
* Number 231; one subject randomized to active treatment who discontinued before taking any medication is not included in the full analysis set.

Number 218.

Unless otherwise noted, all P values are from analysis of variance with terms for treatment and center, baseline score as covariate; no violation of normality.

P values from rank analysis of covariance with terms for treatment, pooled center, and baseline score as a covariate; normality was violated.

.045
.002
1.9
3.5
27.0
29.0
27.0
28.0

13.0
9.0

17.0
15.5

3.79 to 0.05
5.71 to 1.26

.047
.243
2.9
0.1
57.9
3.0
57.1
3.0

77.1
4.0

74.3
4.0

0.02 to 5.77
0.08 to 0.31

.002
.002
.001
0.3
0.3
0.4
4.0
3.9
4.2

DRSP Functional impairment items

More productive
Enhanced social activities
Better relationships
Q-LES-Q
Items 114
Overall life satisfaction
PMTS
Observer rated
Self rated

3.8
3.7
3.9

1.7
1.6
1.7

2.0
1.9
2.2

0.55 to 0.12
0.55 to 0.12
0.64 to 0.20

P
95% CI
Adjusted Mean
Difference
Placebo
Drospirenone/Ethinyl
Estradiol*
Placebo
Outcome Measure

Drospirenone/Ethinyl
Estradiol*

Median Treatment Score

Median Baseline Score

Table 3. Changes in Secondary Outcome Measures With Drospirenone/Ethinyl Estradiol Versus Placebo
498

was one severe adverse event (dysplasia) considered

by the investigator to be possibly related to study drug
in the active-treatment group. Thirty-five subjects
receiving drospirenone/ethinyl estradiol and 9 subjects
in the placebo group discontinued due to adverse
events. The reasons most commonly given by subjects
in the active treatment group for discontinuing the study
included nausea (11 subjects, 31.4%), intermenstrual
bleeding (8 subjects, 22.9%), and asthenia (7 subjects,
20.0%). No deaths were reported in the study.
There were no significant differences in serum
potassium levels between active and placebo groups
during the treatment period (4.3 mEq/L for both
groups). Four subjects receiving active treatment and
one subject in the placebo group had serum potassium levels above the normal range ( 5.5 mEq/L).
One of the 4 subjects receiving drospirenone/ethinyl
estradiol had a serum potassium level of 6.0 mEq/L or
greater, but a repeat serum potassium value 4 days
later was 4.6 mEq/L. None of the subjects with
elevated potassium levels reported arrhythmias, dizziness, palpitations, bradycardia, tachycardia, or syncope at any point in the study.

DISCUSSION
This placebo-controlled, double-blind study shows
that the new drospirenone-containing OCP formulation administered for 24 of 28 days in a cycle ameliorates symptoms associated with premenstrual dysphoric disorder. Active treatment was associated with a
47% reduction in the total Daily Record of Severity of
Problems scale, while the median reductions in distinct items ranged from 45% to 62%. The palliative
effect of OCPs, particularly for physical premenstrual
symptoms, has been suggested by previous epidemiological and nonplacebo-controlled research.7,2123
However, before this trial, it was far less certain that
an OCP formulation would be therapeutic for women
suffering from the more severe condition, premenstrual dysphoric disorder. Moreover, women with
premenstrual dysphoric disorder experience severe
mood symptoms, and OCPs have been thought by
some to worsen or cause symptoms of depression.24,25
Therefore, it is notable that in the current study, active
treatment was associated with a 49% reduction in
premenstrual depression. Our finding showing efficacy for a hormonal contraceptive intervention contrasts with the only 2 published placebo-controlled
studies to evaluate OCP treatment for premenstrual
symptoms. The first study enrolled 82 women with
premenstrual syndrome, and the active treatment was
a triphasic OCP (ethinyl estradiol 35 g plus norethindrone 0.5 mg days 17 and 1721 and 1.0 mg days
8 16).8 Differences between the OCP and placebo
were minimal, although mood worsened in the active-

Drospirenone OCP and Premenstrual Symptoms

OBSTETRICS & GYNECOLOGY

Table 4. Most Common Adverse Events*

No. of Patients (%)

Adverse Event
Intermenstrual bleeding
Headache
Nausea
Breast pain
Upper respiratory infection
Asthenia
Abdominal pain
Sinusitis

Drospirenone/Ethinyl
Estradiol
(n 231)

Placebo
(n 218)

Between-Group
P

58 (25.1)
45 (19.5)
43 (18.6)
31 (13.4)
23 (10.0)
19 (8.2)
12 (5.2)
9 (3.9)

10 (4.6)
44 (20.2)
11 (5.0)
11 (5.0)
24 (11.0)
8 (3.7)
6 (2.8)
11 (5.0)

.001
.946
.001
.004
.834
.067
.281
.718

* Occurring in at Least 5% of either treatment group.

One subject randomized to active treatment, who discontinued before taking any medication, is not included in the full analysis set.

P values from continuity-corrected Pearson 2 test.

treatment group during the hormone-free, postmenstrual period. In the second trial, either placebo or an
OCP with drospirenone 3 mg and ethinyl estradiol 30
g was administered in a 21/7 platform to 82 women
who met premenstrual dysphoric disorder criteria.9
Although active treatment was associated with greater
positive change than with placebo, the between-group
differences did not reach statistical significance, possibly due to the modest sample size in the setting of a
considerable placebo response rate (43%). The current study also used a formulation composed of
drospirenone and ethinyl estradiol, but the dose of
ethinyl estradiol was lower (ie, 20 g rather than 30
g), and the active drug was given for 24 rather than
21 days in a 28-day cycle. These differences in
estrogen dose and shortened drug-free interval may
contribute to the significant differences between active treatment (48.4%) and placebo (36.1%) found in
this study. This finding corresponds to a numberneeded-to-treat of 8 to achieve at least a 50% reduction in symptom severity (ie, response) in one patient.
U.S. Food and Drug Administration (FDA)-approved treatments for premenstrual dysphoric disorder are limited to selective serotonin reuptake inhibitors (SSRIs).13,20,26 In the current study, the overall
effect size estimating the general therapeutic benefit is
roughly similar to that found for SSRIs as reported in
a recent meta-analysis.26 In addition, physical symptoms (eg, those found in item 11 of the Daily Record
of Severity of Problems) responded well to treatment
with drospirenone and ethinyl estradiol. These symptoms are less likely to respond to SSRIs,13 or they
require higher doses for response.27,28
In the current study, as in many studies using
SSRIs,17,20,27,28 the placebo group had high response
rates. Although this could simply be due to subjects
positive expectations, study methods, such as close
contact with study staff and completing daily ratings
VOL. 106, NO. 3, SEPTEMBER 2005

of mood, may have contributed to this nonspecific

response. The latter is particularly important because
mood monitoring is a time-honored therapeutic
intervention in behavioral medicine and contributes
to improvement in emotional symptoms for a number
of mood and anxiety disorders.
Attrition associated with adverse events occurred
in 15% of subjects randomized to active treatment
compared with 4% taking placebo. The most common adverse event in the active treatment group was
intermenstrual bleeding (25.1% versus 4.6% for placebo). Intracyclic bleeding is a frequent occurrence
during the initial cycles of treatment with OCPs
containing low doses of estrogen, an effect that typically decreases and then remains stable after the first
few cycles.29 31 Nausea was more common with active
treatment compared with placebo, but the incidence
of nausea (18.6%) is similar to that found with other
low-dose OCP formulations.32 Relevant to this trial,
complaints of nausea and breast tenderness decrease
after the first few cycles of low-dose OCP use. There
was no difference between the groups with respect to
postbaseline serum potassium levels.
There are several possible limitations to the current study. First, OCPs potentially change the characteristics of the menstrual cycle, which could unblind
study personnel as well as participants. This is of
greater concern for the second and third cycles because subjects and clinicians are more likely to be
unblinded by menstrual characteristics. In this study,
the first set of premenstrual ratings were done before
the first menstrual period. The active treatment-placebo difference occurring in the first study cycle was
at least as large as, if not larger than, that for subsequent study cycles (data available upon request).
Therefore, if unblinding occurred, it either worked
against active treatment or was not of substantial
magnitude. Second, it is possible that drospirenone/

Yonkers et al

Drospirenone OCP and Premenstrual Symptoms

499

ethinyl estradiol shifted the symptomatic period to the

hormone-free interval, as in a prior OCP study.8
However, our analyses of subjects assigned to drospirenone/ethinyl estradiol failed to show differences
between premenstrual medication and premenstrual
placebo days.
In summary, the OCP formulation with drospirenone 3 mg and ethinyl estradiol 20 g administered in a 24/4 regimen was more effective than
placebo at ameliorating premenstrual symptoms in
women with premenstrual dysphoric disorder. This
OCP formulation may have a unique role in women
who both desire contraception and suffer from symptoms of premenstrual dysphoric disorder.
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